The epidemiologic characteristics of adenocarcinoma of the stomach suggest that environmental agents are important in the pathogenesis of this malignancy, and studies of migrants suggest that the significant exposure begins early in life. Helicobacter pylori are gram-negative microaerophilic bacteria that once acquired colonize the human stomach for years or more probably for decades, and are centrally involved in the etiology of most cases of chronic superficial gastritis. Accumulating evidence indicates that H. pylori -induced superficial gastritis may progress over decades to atrophic gastritis, a process well known to be a risk factor for gastric cancer. Four studies in the past year indicate that H. pylori infection is a risk factor for the development of non-cardia (distal) adenocarcinoma of the stomach, with odds ratios ranging from 2.7 to 12.0. However, the vast majority of H. pylori-infected persons never develop gastric cancer. The goal of this study is to define additional factors associated with H. pylori infection that might modulate risk of cancer development. From our previous studies or from collaborators we have obtained serum from patients with gastric cancer and from matched controls, which we would use to address the following specific aims. First, to examine the immunoglobulin subclass response to infection. Our preliminary studies suggest that low specific serum IgA levels are associated with higher levels of gastric inflammation. Second, to determine whether host response to a vacuolating cytotoxin of H. pylori is associated with variations in risk. About 50-60% of H. pylori strains produce the cytotoxin. We have recently purified this toxin and have established an ELISA to detect serum antibodies to it. Third, to determine whether an H. pylori antigen that migrates at approximately 128 kDa is a marker for decreased risk of cancer development. About 80% of H. pylori strains possess the 128 kDa protein and a humoral immune response to this antigen is associated with risk of peptic ulcer disease. Since peptic ulcer disease is negatively correlated with gastric cancer risk, the presence of an H. pylori strain containing the antigen or serum antibodies that recognize it may be associated with protection from cancer development.